Distinct modes of stress granule assembly mediated by the KH-type RNA-binding protein Rnc1.

Genes Cells. 2018 Jul 17;:

Authors: Satoh R, Hara N, Kawasaki A, Takasaki T, Sugiura R

Abstract
We have previously identified the KH-type RNA-binding protein Rnc1 as an important regulator of the posttranscriptional expression of the MAPK phosphatase Pmp1 in fission yeast. Rnc1 localization in response to stress has not been elucidated thus far. Here, we report the dual roles of Rnc1 in assembly of stress granules (SGs), nonmembranous cytoplasmic foci composed of messenger ribonucleoproteins. Rnc1 can localize to poly(A)-binding protein (Pabp)-positive SGs upon various stress stimuli, including heat shock (HS) and arsenite treatment. Furthermore, Rnc1 deletion results in decreased SGs, indicating that Rnc1 is a new component and a regulator of SGs. Notably, Rnc1 translocates to the dot-like structures faster than Pabp, and this stress-induced Rnc1 translocation does not require its RNA-binding ability, as the Rnc1KH1,2,3GD mutant protein with impaired RNA-binding activity forms dots rather more efficiently than the wild-type Rnc1 upon HS. Interestingly, in the absence of stress, Rnc1 overproduction induced massive aggregation of Pabp-positive SGs and eIF2α phosphorylation. In clear contrast, overproduction of the Rnc1KH1,2,3GD mutant failed to induce Pabp aggregation and eIF2α phosphorylation, indicating that Rnc1 overproduction-induced SG assembly requires Rnc1 RNA-binding activity. Collectively, Rnc1 regulates SG assembly, dependently or independently of its RNA-binding activity.

PMID: 30014536 [PubMed - as supplied by publisher]

Uridine triacetate for severe 5-fluorouracil toxicity in a patient with thymidylate synthase gene variation: Potential pharmacogenomic implications.

SAGE Open Med Case Rep. 2018;6:2050313X18786405

Authors: Baldeo C, Vishnu P, Mody K, Kasi PM

Abstract
Adverse drug reactions can be unpredictable. However, pharmacogenomic testing can help identify patients who may be more susceptible to the toxic effects of certain drugs. Genetic variations in the dihydropyrimidine dehydrogenase and thymidylate synthase genes have been shown to increase the risk of 5-fluorouracil toxicity. 5-Fluorouracil toxicity can be life threatening. Fortunately, there is treatment available for 5-fluorouracil toxicity, called uridine triacetate. Although, the indications for its use limit its administration to within 96 h of receiving 5-fluorouracil, we report a case of effective therapy in a patient started on uridine triacetate beyond the recommended 96 h, who was found to carry a thymidylate synthase gene variation but no dihydropyrimidine dehydrogenase mutations. This provides important implications for pharmacogenomic testing.

PMID: 30013790 [PubMed]

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet. 2018 Jul 16;:

Authors: Waage J, Standl M, Curtin JA, Jessen LE, Thorsen J, Tian C, Schoettler N, 23andMe Research Team, AAGC collaborators, Flores C, Abdellaoui A, Ahluwalia TS, Alves AC, Amaral AFS, Antó JM, Arnold A, Barreto-Luis A, Baurecht H, van Beijsterveldt CEM, Bleecker ER, Bonàs-Guarch S, Boomsma DI, Brix S, Bunyavanich S, Burchard EG, Chen Z, Curjuric I, Custovic A, den Dekker HT, Dharmage SC, Dmitrieva J, Duijts L, Ege MJ, Gauderman WJ, Georges M, Gieger C, Gilliland F, Granell R, Gui H, Hansen T, Heinrich J, Henderson J, Hernandez-Pacheco N, Holt P, Imboden M, Jaddoe VWV, Jarvelin MR, Jarvis DL, Jensen KK, Jónsdóttir I, Kabesch M, Kaprio J, Kumar A, Lee YA, Levin AM, Li X, Lorenzo-Diaz F, Melén E, Mercader JM, Meyers DA, Myers R, Nicolae DL, Nohr EA, Palviainen T, Paternoster L, Pennell CE, Pershagen G, Pino-Yanes M, Probst-Hensch NM, Rüschendorf F, Simpson A, Stefansson K, Sunyer J, Sveinbjornsson G, Thiering E, Thompson PJ, Torrent M, Torrents D, Tung JY, Wang CA, Weidinger S, Weiss S, Willemsen G, Williams LK, Ober C, Hinds DA, Ferreira MA, Bisgaard H, Strachan DP, Bønnelykke K

Abstract
Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

PMID: 30013184 [PubMed - as supplied by publisher]

Comprehensive substrate characterization of 22 antituberculosis drugs for multiple solute carrier (SLC) uptake transporters, in vitro.

Antimicrob Agents Chemother. 2018 Jul 16;:

Authors: Parvez MM, Kaisar N, Shin HJ, Lee YJ, Shin JG

Abstract
Substrate potential of antituberculosis drugs on SLC transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for solute carrier (SLC) family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro The result suggested that, ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular-uptake study was performed and the Km values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for OCT1, OCT2, OCTN1, and OCTN2, respectively. Similarly, the Km of prothionamide was 805.8 ± 23.4 μM for OCT1, while the Km values of isoniazid and amoxicillin for OAT3 were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimated in vivo drug-drug interaction indexes, from in vitro transporter inhibition kinetics, for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to be potential for clinical drug interactions. In conclusion, this is the first study that, demonstrated 22 antituberculosis drugs interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions and pharmacokinetics of these antituberculosis drugs.

PMID: 30012768 [PubMed - as supplied by publisher]

Vitamin D and Uterine Fibroids-Review of the Literature and Novel Concepts.

Int J Mol Sci. 2018 Jul 14;19(7):

Authors: Ciebiera M, Włodarczyk M, Ciebiera M, Zaręba K, Łukaszuk K, Jakiel G

Abstract
This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed using the following key words: "uterine fibroid" and "vitamin D". The results of the available studies, published in English from January 2002 up to April 2018, have been discussed. Vitamin D is a group of steroid compounds with a powerful impact on many parts of the human body. This vitamin is believed to regulate cell proliferation and differentiation, inhibit angiogenesis, and stimulate apoptosis. Nowadays, hypovitaminosis D is believed to be a major risk factor in the development of UFs. In many studies vitamin D appears to be a powerful factor against UFs, resulting in inhibition of tumor cell division and a significant reduction in its size, however, the exact role of this compound and its receptor in the pathophysiology of UFs is not fully understood. According to available studies, vitamin D and its analogs seem to be promising, effective, and low-cost compounds in the management of UFs and their clinical symptoms, and the anti-tumor activities of vitamin D play an important role in UF biology. The synergy between vitamin D and selected anti-UF drugs is a very interesting issue which requires further research. Further studies about the biological effect of vitamin D on UF biology are essential. Vitamin D preparations (alone or as a co-drugs) could become new tools in the fight with UFs, with the additional beneficial pleiotropic effect.

PMID: 30011902 [PubMed - in process]

Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD.

Diabetes Care. 2018 02;41(2):348-355

Authors: Shah HS, Morieri ML, Marcovina SM, Sigal RJ, Gerstein HC, Wagner MJ, Motsinger-Reif AA, Buse JB, Kraft P, Mychaleckyj JC, Doria A

Abstract
OBJECTIVE: A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants.
RESEARCH DESIGN AND METHODS: Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data (n = 351) stratified by intervention arm.
RESULTS: A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 × 10-4). This effect was driven by rs57922 (P = 5 × 10-4). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm.
CONCLUSIONS: Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.

PMID: 29183908 [PubMed - indexed for MEDLINE]

Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients.

Breast Cancer Res. 2017 Nov 28;19(1):125

Authors: Helland T, Henne N, Bifulco E, Naume B, Borgen E, Kristensen VN, Kvaløy JT, Lash TL, Alnæs GIG, van Schaik RH, Janssen EAM, Hustad S, Lien EA, Mellgren G, Søiland H

Abstract
BACKGROUND: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients.
METHODS: From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome.
RESULTS: Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14-11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05-13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35-13.58, and HR = 3.70, 95% CI = 1.03-13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information.
CONCLUSIONS: Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.

PMID: 29183390 [PubMed - indexed for MEDLINE]

Genomic Medicine Without Borders: Which Strategies Should Developing Countries Employ to Invest in Precision Medicine? A New "Fast-Second Winner" Strategy.

OMICS. 2017 Nov;21(11):647-657

Authors: Mitropoulos K, Cooper DN, Mitropoulou C, Agathos S, Reichardt JKV, Al-Maskari F, Chantratita W, Wonkam A, Dandara C, Katsila T, Lopez-Correa C, Ali BR, Patrinos GP

Abstract
Genomic medicine has greatly matured in terms of its technical capabilities, but the diffusion of genomic innovations worldwide faces significant barriers beyond mere access to technology. New global development strategies are sorely needed for biotechnologies such as genomics and their applications toward precision medicine without borders. Moreover, diffusion of genomic medicine globally cannot adhere to a "one-size-fits-all-countries" development strategy, in the same way that drug treatments should be customized. This begs a timely, difficult but crucial question: How should developing countries, and the resource-limited regions of developed countries, invest in genomic medicine? Although a full-scale investment in infrastructure from discovery to the translational implementation of genomic science is ideal, this may not always be feasible in all countries at all times. A simple "transplantation of genomics" from developed to developing countries is unlikely to be feasible. Nor should developing countries be seen as simple recipients and beneficiaries of genomic medicine developed elsewhere because important advances in genomic medicine have materialized in developing countries as well. There are several noteworthy examples of genomic medicine success stories involving resource-limited settings that are contextualized and described in this global genomic medicine innovation analysis. In addition, we outline here a new long-term development strategy for global genomic medicine in a way that recognizes the individual country's pressing public health priorities and disease burdens. We term this approach the "Fast-Second Winner" model of innovation that supports innovation commencing not only "upstream" of discovery science but also "mid-stream," building on emerging highly promising biomarker and diagnostic candidates from the global science discovery pipeline, based on the unique needs of each country. A mid-stream entry into innovation can enhance collective learning from other innovators' mistakes upstream in discovery science and boost the probability of success for translation and implementation when resources are limited. This à la carte model of global innovation and development strategy offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive and expensive discovery infrastructures are already in place. Ultimately, broadening our thinking beyond the linear model of innovation will help us to enable the vision and practice of genomics without borders in both developed and resource-limited settings.

PMID: 29140767 [PubMed - indexed for MEDLINE]

In vitro activity of β-lactams in combination with avibactam against multidrug-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Achromobacter xylosoxidans isolates from patients with cystic fibrosis.

J Med Microbiol. 2018 Jul 17;:

Authors: Mathy V, Grohs P, Compain F

Abstract
The in vitro activity of anti-pseudomonal β-lactams in combination with avibactam was evaluated against 54 multidrug-resistant non-fermenting Gram-negative bacilli isolated from cystic fibrosis patients. Avibactam increased and/or restored the antibacterial activities of ceftazidime and aztreonam against Pseudomonas aeruginosa and Stenotrophomonas maltophilia, respectively. No β-lactam-avibactam combination was active against Achromobacter xylosoxidans.

PMID: 30016231 [PubMed - as supplied by publisher]

Addition of hyaluronic acid improves tolerance to 7% hypertonic saline solution in bronchiectasis patients.

Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618787385

Authors: Máiz L, Girón RM, Prats E, Clemente MG, Polverino E, Caño S, Cordovilla R, Dorca J, Peñalver C, Baranda F, Martínez-García MA

Abstract
BACKGROUND: The excessive retention of sputum in the airways, leading to pulmonary infections, is a common consequence of bronchiectasis. Although inhalation of 7% hypertonic saline (HS) has proven an effective method to help remove the mucus, many patients are intolerant of this treatment. The addition of 0.1% hyaluronic acid to HS (HS+HA) could increase tolerance to HS in these patients. The main objective of this study was to evaluate the tolerability of HS+HA in bronchiectasis patients who are intolerant to HS.
METHODS: This prospective, observational, open-label study analysed the outcomes of two groups of bronchiectasis patients previously scheduled to start HS therapy. Patients were assessed for tolerance to HS by a questionnaire, spirometry and clinical evaluation. Patients who were intolerant were evaluated for tolerance to HS+HA approximately one week later. All patients were evaluated for their tolerance to HS or HS+HA 4 weeks after the start of their treatment. Patients were also assessed with quality-of-life and adherence questionnaires, and all adverse events were registered.
RESULTS: A total of 137 bronchiectasis patients were enrolled in the study (age = 63.0 ± 14.7 years; 63.5% women). Of these, 92 patients (67.1%) were tolerant and 45 patients (32.9%) were intolerant to HS. Of the 45 patients intolerant to HS, 31 patients (68.9%) were tolerant and 14 patients (31.1%) intolerant to HS+HA. Of these 31 tolerant patients, 26 (83.9%) could complete the 4-week treatment with HS+HA.
CONCLUSIONS: Two-thirds of bronchiectasis patients that presented intolerance to inhaled HS alone are tolerant to inhaled HS+HA, suggesting that HA improves tolerance to HS therapy.

PMID: 30014774 [PubMed - in process]

CrossTalk opposing view: mucosal acidification does not drive early progressive lung disease in cystic fibrosis.

J Physiol. 2018 Jul 17;:

Authors: Stick SM, Schultz A

PMID: 30014600 [PubMed - as supplied by publisher]

CrossTalk proposal: mucosal acidification drives early progressive lung disease in cystic fibrosis.

J Physiol. 2018 Jul 17;:

Authors: Figueira MF, Webster MJ, Tarran R

PMID: 30014571 [PubMed - as supplied by publisher]

miRNA-Seq identifies a serum miRNA panel, which combined with APRI can detect and monitor liver disease in paediatric Cystic Fibrosis.

Hepatology. 2018 Jul 16;:

Authors: Calvopina DA, Chatfield MD, Weis A, Coleman MA, Fernandez-Rojo MA, Noble C, Ramm LE, Leung DH, Lewindon PJ, Ramm GA

Abstract
Cystic fibrosis (CF)-associated liver disease (CFLD) is a hepatobiliary complication of CF. Current diagnostic modalities rely on non-specific assessments, while liver biopsy is the gold standard to assess severity of fibrosis. MicroRNAs (miRNAs) regulate liver disease pathogenesis and are proposed as diagnostic biomarkers. We investigated the combined use of serum miRNAs and aspartate aminotransferase to platelet ratio (APRI) to diagnose and assess CFLD severity. This was a cross-sectional cohort study of the circulatory miRNA signature of 124 children grouped by clinical, biochemical and imaging assessments as follows: CFLD (n=44), CF patients with no evidence of liver disease (CFnoLD, n=40) and healthy controls (n=40). Serum miRNAs were analysed using miRNA-sequencing. Selected differentially expressed serum miRNA candidates were further validated by qRT-PCR and statistical analysis performed to evaluate utility to predict CFLD and fibrosis severity validated by liver biopsy, alone or in combination with APRI. Serum miR-122-5p, miR-365a-3p and miR-34a-5p levels were elevated in CFLD compared to CFnoLD, while miR-142-3p and let-7g-5p were downregulated in CFLD compared to CFnoLD. Logistic regression analysis combining miR-365a-3p, miR-142-3p and let-7g-5p with APRI showed 21 times greater odds of accurately predicting liver disease in CF with an AUROC=0.91 (sensitivity=83%, specificity=92%; P<0.0001). Expression levels of serum miR-18a-5p were correlated with increasing hepatic fibrosis stage in CFLD (rs =0.56, P<0.0001), showing good diagnostic accuracy for distinguishing severe (F3-4) from mild/moderate fibrosis (F0-2). A unit increase of miR-18a-5p showed a 7-fold increased odds of having severe fibrosis with an AUROC=0.82 (sensitivity=93%, specificity=73%; P=0.004), indicating its potential to predict fibrosis severity.
CONCLUSION: We identified a distinct circulatory miRNA profile in pediatric CFLD with potential to accurately discriminate liver disease and fibrosis severity in children with CF. This article is protected by copyright. All rights reserved.

PMID: 30014495 [PubMed - as supplied by publisher]

Rebuttal from Miriam F. Figueira, Megan J. Webster and Robert Tarran.

J Physiol. 2018 Jul 17;:

Authors: Figueira MF, Webster MJ, Tarran R

PMID: 30014480 [PubMed - as supplied by publisher]

Meconium peritonitis: the role of postnatal radiographic and sonographic findings in predicting the need for surgery.

Pediatr Radiol. 2018 Jul 16;:

Authors: Caro-Domínguez P, Zani A, Chitayat D, Daneman A

Abstract
BACKGROUND: The role of imaging in meconium peritonitis is not limited to establishing a diagnosis; rather, it might also be helpful in determining which neonates require surgery. However, few data in the literature correlate the postnatal radiographic and sonographic findings with the need for surgery.
OBJECTIVE: To compare the role of postnatal radiographic and sonographic findings in predicting the need for surgery in neonates with meconium peritonitis.
MATERIALS AND METHODS: We conducted a retrospective analysis of clinical, imaging and surgical findings in all neonates with meconium peritonitis in the period 1999-2014. We divided the children into operative or non-operative groups and then correlated each group with the presence or absence of the following findings on both the radiographs and sonograms: peritoneal calcification, meconium pseudocyst, intestinal obstruction, volvulus, ascites and pneumoperitoneum.
RESULTS: Thirty-seven neonates (22 males, 15 females) had meconium peritonitis in this period, of whom 23 (62%) required surgery and 14 (38%) were successfully treated non-surgically. None had an antenatal infection and three had cystic fibrosis (8%). Bowel obstruction identified on radiography (12/23, P=0.01) and sonography (9/23, P=0.04) and ascites identified with sonography (7/23, P=0.01) were associated with the need for surgical intervention. The presence of pneumoperitoneum and volvulus were also associated with surgical intervention. There was no significant statistical difference in the number of neonates with diffuse peritoneal calcification who were treated operatively or non-operatively. Four (33%) of the 12 neonates with meconium pseudocysts were successfully treated non-operatively.
CONCLUSION: Imaging findings that predicted the need for surgery were intestinal obstruction, ascites, volvulus and pneumoperitoneum. Neonates with meconium pseudocysts did not require surgery if they were not associated with the described findings. The findings in our patients also indicate that those with diffuse peritoneal calcification as an isolated finding can be successfully treated non-operatively.

PMID: 30014199 [PubMed - as supplied by publisher]

Impact of an antifungal stewardship programme in a tertiary respiratory medicine setting: A prospective real-world study.

Antimicrob Agents Chemother. 2018 Jul 16;:

Authors: Nwankwo L, Periselneris J, Cheong J, Thompson K, Darby P, Leaver N, Schelenz S, Armstrong-James D

Abstract
There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to healthcare systems.An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice monthly multidisciplinary team meetings and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team.During the first eighteen months of implementation the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated followed by asthma and interstitial lung disease. There was a significant, sustained reduction in monthly antifungal expenditure (p=0.005) by £130,000 per month. There was also a significant reduction in antifungal use measured as Defined Daily Dose/100 bed days (p=0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (p=0.086) and a significant increase in therapeutic levels of posaconazole (p<0.0001).This study shows that an effective antifungal stewardship programme can significantly reduce expenditure in a specialist respiratory service.

PMID: 30012769 [PubMed - as supplied by publisher]

Characterization of the AmpC β-lactamase from Burkholderia multivorans.

Antimicrob Agents Chemother. 2018 Jul 16;:

Authors: Becka SA, Zeiser ET, Barnes MD, Taracila MA, Nguyen K, Singh I, Sutton GG, LiPuma JJ, Fouts DE, Papp-Wallace KM

Abstract
Burkholderia multivorans is a member of the Burkholderia cepacia complex, a group of >20 related species of nosocomial pathogens that commonly infect individuals suffering from Cystic Fibrosis. β-Lactam antibiotics are recommended as therapy for infections due to B. multivorans, which possesses two β-lactamase genes, blapenA and blaAmpC PenA is a carbapenemase with a substrate profile similar to the Klebsiella pneumoniae carbapenemase (KPC); in addition, expression of PenA is inducible by β-lactams in B. multivorans Herein, we characterize AmpC from B. multivorans ATCC 17616. AmpC possesses only 38-46% protein identity to non-Burkholderial AmpCs (e.g., PDC-1, CMY-2). Within 49 clinical isolates of B. multivorans, we identified 27 different AmpC variants. Some variants possessed single amino acid substitutions within critical active site motifs (Ω-loop and R2 loop). Purified AmpC1 demonstrated minimal measurable catalytic activity towards β-lactams (i.e., nitrocefin and cephalothin). Moreover, avibactam was a poor inhibitor of AmpC1 (Ki app >600 μM) and the acyl-enzyme complex formation with AmpC1 was slow, likely due to lack of productive interactions with active site residues. Interestingly, immunoblotting using a polyclonal anti-AmpC antibody revealed that protein expression of AmpC1 was inducible in B. multivorans ATCC 17616 after growth in sub-inhibitory concentrations of imipenem (1 μg/ml). The AmpC is a unique inducible class C cephalosporinase that may play an ancillary role in B. multivorans compared to PenA, which is the dominant β-lactamase in B. multivorans ATCC 17616.

PMID: 30012762 [PubMed - as supplied by publisher]

Pilates in noncommunicable diseases: A systematic review of its effects.

Complement Ther Med. 2018 Aug;39:114-130

Authors: Miranda S, Marques A

Abstract
OBJECTIVES: Chronic cardiovascular diseases, cancer, chronic respiratory diseases and diabetes are the four major groups of non-communicable diseases (NCDs) and the main cause of mortality worldwide. Pilates has been described as an effective intervention to promote healthy behaviors and physical activity in people with chronic diseases. However, the evidence of its effects in NCDs have not been systematized. We investigated the effects of Pilates in the four major groups of NCDs.
DESIGN: A systematic review was performed. Searches were conducted on Cochrane Library, EBSCO, PubMed, Science Direct, Scopus and Web of Science databases. Studies were rated with the quality assessment tool for quantitative studies. As a meta-analysis was not possible to conduct, a best-evidence synthesis was used.
RESULTS: Twelve studies, mostly of moderate quality, were included with 491 participants (78.6% females; age range 13-70 years old) with breast cancer (n = 3), diabetes (n = 3), chronic stroke (2 years post stroke) (n = 2), chronic obstructive pulmonary disease (n = 1), cystic fibrosis (n = 1), heart failure (n = 1) and arterial hypertension (n = 1). The best-evidence synthesis revealed strong evidence for improving exercise tolerance; moderate evidence for improving symptoms, muscle strength and health-related quality of life and limited or conflicting evidence on vital signs, metabolic parameters, body composition, respiratory function, functional status, balance, flexibility and social support.
CONCLUSIONS: Pilates should be considered for patients with NCDs, as it improves exercise tolerance. Future studies with robust methodologies are still needed to clarify its effectiveness on outcomes with moderate, limited or conflicting evidence and to establish the most suitable intervention protocol.

PMID: 30012382 [PubMed - in process]

Burkholderia cepacia complex Infections: More Complex than the Bacterium Name Suggest.

J Infect. 2018 Jul 13;:

Authors: Sfeir MM

Abstract
Burkholderia cepacia complex (Bcc) is an emerging pathogen causes life-threatening infections in cystic fibrosis patients. This narrative review aims to highlight an update on the epidemiology, the microbiological diagnostic methods, the antimicrobial resistance mechanisms, and the most current as well the promising therapeutic options for Bcc. Although Bcc plays a role in crop growth due to its fungicidal activity and pesticide metabolizer, it has been frequently implicated in outbreaks in the United States and Worldwide due to contaminated medicines or medical devices. Phenotypic methods of microbial identification often lack sensitivity. Consequently, the diagnosis is mainly based on molecular testing which is critical for species identification. Disc diffusion is a poorly reproducible method for antibiotic susceptibility testing of Bcc when compared to broth microdilution, agar dilution or Etest. Bcc is naturally resistant to many antimicrobialagents including carboxypenicillins, polymyxin, and often, aminoglycosides due to the efflux pump activity. Treatment is often based on antimicrobial susceptibility data. However, trimethoprim-sulfamethoxazole, meropenem, doripenem, doxycycline, minocycline, and ceftazidime have been shown to be among the most active antimicrobial agents to date. Further studies are needed to compare the current antimicrobial agents and to study new inhibitors of the different efflux pumps implicated in the resistance of Bcc to antibiotics. Furthermore, harmonization of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines is highly important to fight against the rapidly emerging resistant bacteria e.g. Bcc.

PMID: 30012345 [PubMed - as supplied by publisher]

Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.

J Pathol. 2018 Jul 17;:

Authors: Chedgy EC, Vandekerkhove G, Herberts C, Annala M, Donoghue AJ, Sigouros M, Ritch E, Struss W, Konomura S, Liew J, Parimi S, Vergidis J, Hurtado-Coll A, Sboner A, Fazli L, Beltran H, Chi KN, Wyatt AW

Abstract
Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment-related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM or MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options. This article is protected by copyright. All rights reserved.

PMID: 30015382 [PubMed - as supplied by publisher]